As the gene therapy field moves towards human clinical trials, it is becoming clear that efficient gene transfer will likely determine overall success of these approaches. Thus, development of vectors with the capacity for in vivo gene delivery has become paramount. Of the available vector systems capable of in vivo gene delivery, adenoviral vectors seem most promising. Thus, the generation of a vector which can specifically target these cells based upon their inherent molecular abnormalities would be significant. Recently, it has become feasible to design adenoviral vectors which can selectively transduce tumor cells. While preliminary work in this area is encouraging, a flexible approach to adenoviral vector retargeting must be devised. In this regard, we have developed a universal, small molecule, molecular binding system which combines any two molecular entities. This system will be used to generate tropism-modified adenoviral vectors through ablation of endogenous adenoviral tropism and introduction of novel binding determinants. This strategy has become successful in feasibility studies. The development of a performance optimized, universal recombination system is proposed. PROPOSED COMMERCIAL APPLICATION Research will lead to a universal small molecule linkage system designed to allow any desired ligand to be appended to a gene packaging system. This will lead to separation of gene package from targeting ligand as separate but complementary products. Targeted gene therapy products have an estimated market potential of $8B in cancer alone.